In light of our previous observation of higher levels of cerebrospinal fluid (CSF) amyloid beta-42 (Aβ42) and CSF/serum albumin ratio in major depressive disorder (MDD), we analyzed two additional CSF biomarkers reflecting neurodegeneration—neurofilament protein light (NFL) and glial fibrillary acidic protein (GFAp)—in relationship to prevalent geriatric depression. Neuropsychiatric, physical, and lumbar puncture examinations, with DSM-III-R-based depression diagnoses and measurement of CSF levels of NFL and GFAp, were evaluated among a population-based sample of 78 elderly women (mean age, 73.9±3.2 years) without dementia for at least 10 years after CSF collection. Eleven (13.1%) women had MDD, and higher levels of NFL compared with women without depression. A multivariate model including age, NFL, Aβ42 and the CSF/serum albumin ratio showed that each biomarker was independently and positively associated with MDD, and that this biomarker profile explained more variation in the model compared with single or combined biomarkers. A CSF profile with higher levels of NFL, Aβ42, and CSF/serum albumin ratio may indicate neuropathological and vascular events in depression etiology. This contrasts with the well-characterized pattern of low Aβ42, higher CSF/serum albumin ratio, and higher NFL in Alzheimer's disease.

OBJECTIVE: Cerebrospinal fluid (CSF) biomarkers including the 42 amino-acid form of beta-amyloid (Abeta42), total tau protein (T-tau), and the CSF/serum albumin ratio are markers of brain pathology and metabolism. Abeta42 and T-tau are sometimes used to discriminate geriatric depression from mild forms of Alzheimer disease (AD) in clinical studies. However, studies focusing on the relationship between these CSF biomarkers and geriatric depression are lacking. METHODS: This was a cross-sectional study with a population-based sample of 84 nondemented elderly women in Sweden. Measurements included neuropsychiatric, physical, and lumbar puncture examinations, with Diagnostic and Statistical Manual of Mental Disorders, Third Revision-based depression diagnoses and measurement of CSF levels of Abeta42, T-tau, albumin, and serum albumin. RESULTS: Fourteen women (mean age: 72.6 years) had any depression (11 with major depressive disorder [MDD]). Compared to women without depression, women with MDD had higher levels of Abeta42 and the CSF/serum albumin ratio. The CSF/serum albumin ratio was also higher in women with any depression. No differences in T-tau were observed; however, T-tau increased with age. CONCLUSION: Higher levels of CSF Abeta42 were observed among elderly depressed women, in contrast to lower levels usually observed in AD, indicating potential neuropathological differences between the two disorders. Higher CSF/serum albumin ratios observed in depressed women point to potential vascular processes.

BACKGROUND: Low levels of cerebrospinal fluid (CSF) beta-amyloid 1-42 (Abeta42) and high total tau (T-tau) are diagnostic for manifest Alzheimer's disease. It is not known, however, whether these biomarkers may be risk indicators for cognitive decline in otherwise healthy older people. METHODS: The longitudinal relationship between CSF markers, Abeta42 and T-tau, measured in 1992, and change in Mini-Mental State Examination (deltaMMSE) score between 1992 and 2002 were investigated in 55 women (aged 70-84 years, mean (SD) MMSE score = 28.3 (1.5)), who were participants in the Prospective Population Study of Women in Gothenburg, Sweden. These women did not have dementia when they experienced lumbar puncture in 1992-3. RESULTS: Over the 8-year follow-up period, deltaMMSE (range = +3 to -21 points) was correlated with Abeta42 (Spearman's r = 0.40, p = 0.002), such that lower levels of Abeta42 were related to greater decline. This was also observed after excluding 4 women who developed dementia between 1992 and 2002 (Spearman's r = 0.34, p = 0.019). A multivariate logistic regression model predicting a decline of > or = 5 points on the MMSE (observed in six women), or a risk of developing dementia over the 8-year follow-up period (observed in four women), including age, education, Abeta42 and T-tau as covariates, showed that Abeta42 was the sole predictor of significant cognitive decline or dementia (OR per 100 pg/ml Abeta42 = 2.24, 95% CI 1.19 to 4.22, p = 0.013). CONCLUSIONS: Low levels of CSF Abeta42 may predict cognitive decline among older women without dementia.

OBJECTIVE: We explored the relationship between adiposity factors measured during mid-life and blood-brain barrier (BBB) integrity measured via the cerebrospinal fluid/serum (CSF/S) albumin ratio in late life. Adiposity factors included body mass index and blood levels of sex hormone binding globulin (SHBG) and leptin. Design. Retrospective analyses over 24 years within a longitudinal study. SETTING: Population-based sample. Subjects. Eighty-one women. MAIN OUTCOME MEASURES: CSF/S albumin ratio. RESULTS: The CSF/S albumin ratio measured at age 70-84 years was higher amongst women who were overweight or obese (6.50 +/- 2.79 vs. 5.23 +/- 1.61, age-adjusted P = 0.012), and was inversely correlated with SHBG (age-adjusted r = -0.321, P < 0.005) at age 46-60 years. In stepwise regression models, SHBG predicted the CSF/S albumin ratio (beta = -0.017, R2 = 0.107, P = 0.007). The best model (R2 = 0.187) predicting CSF/S albumin ratio included SHBG, age group (age 46 years versus >46), overweight or obesity, and an age group by SHBG interaction. CONCLUSIONS: Lower levels of SHBG in mid-life were related to worse BBB integrity in women after 24 years in late life, even considering other adiposity factors. SHBG may be important for understanding sex hormone-mediated mechanisms in brain health or as an independent marker of adipose tissue, the largest endocrine organ.

The renin-angiotensin system (RAS) may play a role in dementia pathogenesis because of its effects on vascular and metabolic homeostasis, amyloid metabolism, and learning and memory. The angiotensin-converting enzyme (ACE), a pivotal RAS protein, is encoded for by a gene containing a functional ID variant, which has been related to dementia risk. We examined the relationship between the ACE Insertion Deletion (ACE ID) variant and dementia with consideration for metabolic phenotypes, age and APOEepsilon4 using a population-based, cross-sectional sample of 891 Swedish women and men aged 70-92 years, of whom 61 people were demented. The odds of dementia was two-fold higher among those with ACE II genotype, and ranged from 2.18 to 4.35 among those with dementia onset <or=70 years, an APOEepsilon4 allele, systolic blood pressure <160 mmHg, body mass index <25 kg/m(2), and in women only, waist circumference <or=88 cm and hip circumference <101 cm. Variations among reports on the relationship between the ACE ID polymorphism and dementia may be due to lack of consideration for gene-gene and gene-phenotype associations.

Alzheimer&#39;s disease (AD) and age-related cataract, disorders characterized by protein aggregation causing late-onset disease, both involve oxidative stress. We hypothesize that common variants of NFE2L2 and KEAP1, the genes encoding the main regulators of the Nrf2 system, an important defence system against oxidative stress, may influence risk of AD and/or age-related cataract. This case-control study combines an AD material (725 cases and 845 controls), and a cataract material (489 cases and 182 controls). Genetic variation in NFE2L2 and KEAP1 was tagged by eight and three tag single nucleotide polymorphisms (SNPs), respectively. Single SNPs and haplotypes were analyzed for associations with disease risk, age parameters, MMSE and AD cerebrospinal fluid biomarkers. NFE2L2 and KEAP1 were not associated with risk of AD or cataract. However, one haplotype allele of NFE2L2 was associated with 2 years earlier age at AD onset (pc 0.013) and 4 years earlier age at surgery for posterior subcapsular cataract (p(c) = 0.019). Another haplotype of NFE2L2 was associated with 4 years later age at surgery for cortical cataract (p(c) = 0.009). Our findings do not support NFE2L2 or KEAP1 as susceptibility genes for AD or cataract. However, common variants of the NFE2L2 gene may affect disease progression, potentially altering clinically recognized disease onset. (C) 2010 Elsevier Ireland Ltd. All rights reserved.